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CN101939003A - Pharmaceutical compositions of entacapone, levodopa and carbidopa with improved bioavailability - Google Patents

Pharmaceutical compositions of entacapone, levodopa and carbidopa with improved bioavailability Download PDF

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Publication number
CN101939003A
CN101939003A CN2009801045488A CN200980104548A CN101939003A CN 101939003 A CN101939003 A CN 101939003A CN 2009801045488 A CN2009801045488 A CN 2009801045488A CN 200980104548 A CN200980104548 A CN 200980104548A CN 101939003 A CN101939003 A CN 101939003A
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entacapone
pharmaceutical composition
levodopa
compositions
carbidopa
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M·塔尔沃
R·卡珀
M·马沙卡
G·K·简恩
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Wockhardt Research Centre
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Wockhardt Research Centre
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
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    • A61K31/275—Nitriles; Isonitriles
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

The present invention relates to single oral dose pharmaceutical compositions comprising a combination of entacapone, levodopa and carbidopa, or salts thereof along with one or more sugar alcohols, wherein the entacapone is co-micronized with one or more sugar alcohols. The composition of the invention exhibits bioequivalence to commercially available entacapone, levodopa and carbidopa combination formulation marketed under the trade name Stalevo200 TM. The invention also relates to processes for making such compositions.

Description

The pharmaceutical composition of entacapone, levodopa and carbidopa that bioavailability is improved
Technical field
The present invention relates to comprise entacapone, levodopa and carbidopa or its salt single port clothes dose drug compositions, wherein the common micronization of entacapone and one or more sugar alcohols together with the combination of one or more sugar alcohols.On compositions of the present invention and the market with Stalevo200 Entacapone, levodopa and carbidopa combination preparation that the name of an article is sold have bioequivalence.The invention still further relates to this type of method for compositions of preparation.
Background technology
Entacapone is a kind of catechol ortho position transmethylase (COMT) inhibitor, is the chemical compound of a kind of nitro-catechol-structure, is used for the treatment of parkinson disease as the complementary therapy of levodopa/carbidopa therapy.From chemically, entacapone is (E)-2-cyano group-3-(3,4-dihydroxy-5-nitrobenzophenone)-N, N-diethyl-2-acrylamide, and structural formula is as follows:
Figure BPA00001194825400012
Carbidopa is a kind of aromatic amino acid decarboxylation inhibitor, is the crystalline chemical compound of a kind of white, is slightly soluble in water.From chemically, it be (-)-L-(α-diazanyl-(Alpha-Methyl-β-(3, the 4-dihydroxy benzenes) propanoic acid monohydrate, structural formula is as follows:
Figure BPA00001194825400013
Levodopa is a kind of aromatic amino acid, is the crystalline chemical compound of a kind of white, is slightly soluble in water.From chemically, it be (-)-L-(pantonine-(3, the 4-dihydroxy benzenes) propanoic acid, structural formula is as follows:
Figure BPA00001194825400021
Entacapone belongs to the IV class medicine in the bio-pharmaceutical taxonomic hierarchies, causes the problem of low solubility, low dissolution rate thereby low bioavailability.
U.S. Pat 4963590 provides a kind of pharmaceutical composition that comprises entacapone and pharmaceutically acceptable carrier.
United States Patent (USP) the 6500867th and disclosed the oral solid drug tablet composition that comprises entacapone, levodopa and carbidopa or its pharmaceutically acceptable salt or hydrate and pharmaceutically acceptable excipient for No. 6797732.These two patents all disclose, and cause stability problem when carbidopa, levodopa and entacapone mix, and do not reach desired therapeutic effect.On the other hand, when when levodopa and entacapone are isolated the carbidopa of considerable part, preparation shows preferably stability and has reached desired therapeutic effect.
U.S. Pat 6599530 provides a kind of compositions of tablet form of oral compacting, 6% the croscarmellose sodium that it comprises the pharmaceutically acceptable salt of entacapone, nitecapone or entacapone, nitecapone and accounts for said composition weight at least.
U.S. Patent application US20060222703 has described entacapone, carbidopa and the levodopa combination of oral medication that is added with microcrystalline Cellulose and starch, and three all active ingredients mix simultaneously.Said composition is by the preparation of compacting comminution granulation.This application has been described the defective relevant with wet granulation, comprise owing in wet granulation, used water to make the compositions loss of stability, made levodopa, carbidopa and entacapone stripping reduce.
Though know all in the presence of surfactant or sugar material carried out micronization or grind improving its dissolubility that these parameters are not always sufficient.Therefore for example, the bioavailability deficiency of micronization Progesterone should be for example improved by disperseing in Brazil wax.Such technology sees International Patent Application WO 8902742.Thereby, seemingly unpredictable by micronization or grind the Substance Properties of handling, especially its dissolubility and bioavailability, may obtain the result of contradiction.
There is a large amount of prior art lists of references to disclose sugar alcohol such as mannitol, Sorbitol etc., promptly in mouth, gives the application of the reagent of oral cavity cooling feeling under the situation of disintegrating tablet as the filler in the preparation or as the sensory signal agent.For example, International Patent Application WO 2007080601, WO2007001086, WO2006057912; European patent EP 589981B1, EP906089B1, EP1109534B1; U.S. Pat 6328994 and U.S. Patent application US20070196494, US20060240101 and US20060057199.Agent is used in the preparation of disintegrate in most of mouthfuls sugar alcohol as mannitol as sensory signal, and not be used in the conventional quick releasing formulation, because disintegrating preparations disintegrate in the oral cavity in the mouth, rather than disintegrate in gastrointestinal tract as conventional fast-release tablet.
Summary of the invention
A broad aspect of the present invention provides a kind of single port clothes dose drug compositions that comprises entacapone, levodopa and carbidopa or its salt together with the combination of one or more sugar alcohols, the wherein common micronization of entacapone and one or more sugar alcohols.
The embodiment of pharmaceutical composition can comprise with the next item down or multinomial feature.For example, pharmaceutical composition can further comprise one or more pharmaceutically acceptable excipient.Pharmaceutically acceptable excipient comprises one or more binding agents, filler, lubricant, disintegrating agent, fluidizer and so on.
Another broad aspect provides a kind of single port clothes dose drug compositions that comprises entacapone, levodopa and carbidopa or its salt together with the combination of one or more sugar alcohols, the common micronization of entacapone wherein and one or more sugar alcohols; Wherein the stripping feature of said composition is that at least 80% entacapone discharged in 30 minutes; Rate of release is 5.5 phosphate buffer with 900 milliliters of pH, and temperature is at 37 ℃ ± 0.5 ℃, by instrument 2 (Apparatus 2) measure (USP, dissolution, the oar method, 50rpm).
Another broad aspect provides a kind of method of pharmaceutical compositions, and this method comprises: a) with entacapone or its salt and the common micronization of one or more sugar alcohols and with one or more pharmaceutically acceptable mixed with excipients and granulate; B) with carbidopa and levodopa and one or more pharmaceutically acceptable mixed with excipients and granulation; C) step a) is mixed with the mixture of step b); And d) make the mixture of step c) form pharmaceutical dosage form.
The embodiment of pharmaceutical composition can comprise with the next item down or multinomial feature.For example, pharmaceutically acceptable excipient can comprise one or more binding agents, filler, lubricant, disintegrating agent, fluidizer and so on.
Another broad aspect provides a kind of single port clothes dose drug compositions that comprises entacapone, levodopa and carbidopa or its salt together with the combination of one or more sugar alcohols, the common micronization of entacapone wherein and one or more sugar alcohols; Said composition aspect the infiltration rate of entacapone and degree with Stalevo200 The there was no significant difference as a result that conventional entacapone, levodopa and Lodosyn obtained that the name of an article is sold.
The embodiment of pharmaceutical composition can comprise with the next item down or multinomial feature.For example, pharmaceutical composition can further comprise one or more pharmaceutically acceptable excipient.Pharmaceutically acceptable excipient can comprise one or more binding agents, filler, lubricant, disintegrating agent, fluidizer and so on.
Describe one or more embodiments of the present invention in detail in the following content.By description and claims, be realized that other features, objects and advantages of the present invention.
Detailed Description Of The Invention
The inventor notices, as sugar alcohols such as mannitol or Sorbitol with other known water-fast medicine as fenofibrate, irbesartan, when Aripiprazole uses, no matter be as physical mixture or with the form of complex, can not cause the dissolubility of above-mentioned insoluble drug to significantly improve.According to another observation, no matter these medicines individualism in preparation still is with sugar alcohol, and the dissolubility of these insoluble drugs or release percentage ratio are all without any significant difference.
The inventor surprisedly finds when the combination preparation to entacapone, levodopa and carbidopa makes a search work, when with entacapone and one or more sugar alcohols altogether during micronization, cause the dissolubility of entacapone and discharge percentage ratio not carrying out being significantly increased for the combination preparation of micronized altogether entacapone, levodopa and carbidopa with sugar alcohol with respect to entacapone.
Stalevo 200 In 30 minutes, discharge about 70% entacapone, and pharmaceutical composition of the present invention discharged about 85% entacapone in 30 minutes.Thisly discharge percentile significantly improving at entacapone and improved wettability, dissolubility, thereby improved the release percentage rate.
The inventor is also noted that pharmaceutical composition of the present invention and commercially available entacapone, carbidopa and levodopa combination, and (Stalevo 200 ) be bioequivalent.
" bioequivalence " is according to FDA's regulation and control guide, maximal plasma concentration (C Max) and area under curve (AUC) by 90% confidence interval (CI) between 0.80 and 1.25, perhaps according to EMEA regulation and control guide, AUC presses 90%CI between 0.80 to 1.25 and C MaxPress 90%CI between 0.70 to 1.43.
The bioequivalence Journal of Sex Research is at Stalevo 200
Figure BPA00001194825400053
And carry out between the present composition.The project of research monitoring has test products (compositions of the present invention) and benchmark product, and (Stalevo 200
Figure BPA00001194825400054
) C Max, AUC and the time (T that reaches maximal plasma concentration Max).Table 3 provides compositions of the present invention and Stalevo 200
Figure BPA00001194825400055
The bioequivalence data.Table 4 provides in 90% confidence interval about the bioequivalence data of test-benchmark ratio (T/R ratio).
In single port clothes dose drug compositions of the present invention, the entacapone of considerable part or its salt are separated from the mixture of levodopa and carbidopa or their salt; Perhaps the carbidopa of considerable part or its salt are separated from the mixture of levodopa and entacapone or their salt; Perhaps carbidopa, entacapone or levodopa exist in mixture simultaneously.
" considerable part " of term entacapone/carbidopa/levodopa or their salt is meant any one stability and/or the Ta Kapeng/carbidopa/levodopa of dissolution and therapeutic effect or its bioavailability or the amount of its salt among Ta Kapeng/carbidopa/levodopa in single port clothes dosage Ta Kapeng, carbidopa and the levodopa combination of not disturbing here.
The feature of the pharmacokinetic curve of the present composition is maximal plasma concentration (C Max) about 1.1 to about 2.0 μ g/ml; Reach the time (T of maximal plasma concentration Max) at about 1.6 to about 3.5 hours; Area (AUC under the Cot curve 0-t) and (AUC Φ) about 1.80 to about 3.50 μ g.h/ml.
With Stalevo 200
Figure BPA00001194825400061
What obtained compares, in 90% confidence interval, and the area (AUC of the present composition under Cot curve 0-tAnd/or AUC Φ) value is between 0.70 and 1.30, the maximal plasma concentration (C of the present composition Max) be worth between 0.60 and 1.40.
Suitable sugar alcohol comprises one or more in mannitol, maltose alcohol, maltol, Sorbitol, lactose, the xylitol etc.
In pharmaceutical composition of the present invention, for sugar alcohol, the amount of entacapone can be to make mol ratio between entacapone and the sugar alcohol between about 1: 1 to 10: 1.
Micronization can be undertaken by suitable means known in the art altogether, includes but not limited in nanometer mill, ball milling, pulverizer mill, vibromill, sand milling, pearl mill, jet mill, the Ultrasonic Pulverization etc. one or more.
The entacapone and the sugar alcohol average particle size that obtain after being total to micronization processes can be less than 30 microns.
This pharmaceutical composition can divide two parts preparation.First comprises entacapone and the common micronization of one or more suitable sugar alcohols, granulates with binder solution, and make particle drying.Dried granule can milled processed and with other suitable pharmaceutically acceptable mixed with excipients.
Second portion comprises with levodopa and carbidopa and one or more suitable pharmaceutically acceptable mixed with excipients and with binder solution granulates.With particle drying.Dried granule can milled processed and with one or more pharmaceutically acceptable mixed with excipients.
Entacapone particle and levodopa and carbidopa particle can be mixed with suitable dosage form, such as monolayer tablet, bilayer tablet, tablet cover tablet, capsule sheet, tabloid, capsule, capsule set tablet, capsule set granule, pill, capsule set pill, powder.In addition, powder or granule can be handled through suspending and obtain pharmaceutically acceptable oral suspensions.
This pharmaceutical composition can further comprise one or more pharmaceutically acceptable excipient.Pharmaceutically acceptable excipient comprises binding agent, filler, lubricant, disintegrating agent and fluidizer.
Suitable bonding comprises one or more in polyvidone, starch, stearic acid, natural gum, the hydroxypropyl emthylcellulose etc.
Suitable filler comprises one or more in microcrystalline Cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, Kaolin, dried starch, the powdered sugar etc.
Examples of suitable lubricants comprises one or more in magnesium stearate, zinc stearate, calcium stearate, stearic acid, stearyl fumarate, the hydrogenated vegetable wet goods.
Suitable fluidizer comprises one or more in silica sol, Pulvis Talci or the corn starch etc.
Suitable disintegrants comprises that starch, croscarmellose are received, in polyvinylpolypyrrolidone, primojel etc. one or more.
Embodiment 1: the composition of each batch of material sees Table 1.Following preparation is the representative of the preferred embodiment for the present invention.Details are as follows in the preparation of embodiment 1.
Table 1: levodopa, carbidopa and entacapone compositions
Figure BPA00001194825400081
Step: this pharmaceutical composition can divide two parts preparation.First comprise entacapone mixed with mannitol and through one or more circulations with pre-composition micronization altogether.Starch, croscarmellose sodium, primojel mix in high-speed mixing granulating machine, granulate with the polyvidone aqueous solution, and granule is dry in fluidized bed dryer.
Second portion comprises levodopa, carbidopa is mixed with starch, granulates with the polyvidone aqueous solution, and granule is dry in fluidized bed dryer.Exsiccant entacapone and levodopa, carbidopa granule are merged, mix in the bipyramid mixing machine with primojel, mannitol, microcrystalline Cellulose and Pulvis Talci then, with magnesium stearate as lubricant.Utilize proper implements that Opadry (opadry) aqueous solution coating is also used in lubricated granule compacting in flakes.
Table 2:Stalevo 200
Figure BPA00001194825400091
With the stripping data of the present composition of embodiment 1 preparation relatively.Use USP 2 type instruments (rpm 50), wherein use 37 ℃ ± 0.5 ℃, pH be 5.5 1000 ml phosphate buffers as medium, determine drug release rate.
Figure BPA00001194825400092
Table 3 compositions of the present invention and Stalevo 200
Figure BPA00001194825400093
Bioequivalence data about the pharmacokinetic parameter aspect.
Figure BPA00001194825400094
Table 4 is in 90% confidence interval, and (Stalevo 200 about test (present composition)-benchmark
Figure BPA00001194825400095
) than the bioequivalence data of (T/R than)
Figure BPA00001194825400101
Though described the present invention according to the specific embodiment, some changes and equivalents is significantly to those skilled in the art and should comprises within the scope of the invention.

Claims (19)

1. single port clothes dose drug compositions, it comprises the combination together with one or more sugar alcohols of entacapone, levodopa and carbidopa or its salt; Wherein said entacapone and one or more sugar alcohols be micronization altogether.
2. pharmaceutical composition as claimed in claim 1, the mol ratio of wherein said entacapone and sugar alcohol are about 1: 1 to 10: 1.
3. pharmaceutical composition as claimed in claim 1, wherein said sugar alcohol comprises one or more in mannitol, maltose alcohol, maltol, Sorbitol, lactose and the xylitol.
4. pharmaceutical composition as claimed in claim 1, the particle mean size of wherein said common micronized entacapone and sugar alcohol mixtures is less than 30 μ.
5. pharmaceutical composition as claimed in claim 1, wherein said compositions comprise one or more in tablet, capsule, powder, dish agent, capsule sheet, granule, pill, capsule set granule, tabloid, capsule set tabloid, capsule set pill and the capsule bag.
6. pharmaceutical composition as claimed in claim 1 also comprises one or more pharmaceutically acceptable excipient.
7. compositions as claimed in claim 1, the wherein mixture separation of the entacapone of considerable part or its salt and levodopa and carbidopa or their salt.
8. compositions as claimed in claim 1, the wherein mixture separation of the carbidopa of considerable part or its salt and entacapone and levodopa or their salt.
9. compositions as claimed in claim 1, wherein the stripping feature of said composition is that at least 80% entacapone discharged in 30 minutes; Described rate of release is 5.5 phosphate buffer with 900 milliliters of pH, and temperature is at 37 ℃ ± 0.5 ℃, by instrument 2 measure (USP, dissolution, the oar method, 50rpm).
10. compositions as claimed in claim 1, wherein said composition prepares by following steps: a) with entacapone or its salt and one or more sugar alcohols micronization and with other pharmaceutically acceptable mixed with excipients and granulate altogether; B) with carbidopa and levodopa and other pharmaceutically acceptable mixed with excipients and granulation; C) step a) is mixed with the mixture of step b); And d) make the mixture of step c) form pharmaceutical dosage form.
11. single port clothes dose drug compositions, it comprises the combination together with one or more sugar alcohols of entacapone, levodopa and carbidopa or its salt; Wherein said entacapone and one or more sugar alcohols be micronization altogether; Said composition aspect the infiltration rate of entacapone or its salt and degree two or one of them aspect with Stalevo200
Figure FPA00001194825300021
The result that entacapone, levodopa and Lodosyn obtained that the name of an article is sold does not have significant difference.
12. pharmaceutical composition as claimed in claim 11, the maximal plasma concentration (C of wherein said compositions Max) be that about 1.1 μ g/ml are to about 2.0 μ g/ml.
13. pharmaceutical composition as claimed in claim 11, wherein said compositions reach the time (T of maximal plasma concentration Max) be about 1.6 hours to about 3.5 hours.
14. pharmaceutical composition as claimed in claim 11, area (AUC under the Cot curve of wherein said compositions 0-t) and (AUC Φ) be about 1.80 to about 3.50 μ g.h/ml.
15. pharmaceutical composition as claimed in claim 11, wherein the mol ratio of entacapone and sugar alcohol is about 1: 1 to 10: 1.
16. pharmaceutical composition as claimed in claim 11, wherein said sugar alcohol comprises one or more in mannitol, maltose alcohol, maltol, Sorbitol, lactose and the xylitol.
17. pharmaceutical composition as claimed in claim 11, wherein said micronized entacapone altogether and sugar alcohol mixtures particle mean size are less than 30 μ.
18. pharmaceutical composition as claimed in claim 11, wherein said compositions comprise in tablet, capsule, powder, dish agent, capsule sheet, granule, pill, capsule set granule, tabloid, capsule set tabloid, capsule set pill and the capsule bag one or more.
19. pharmaceutical composition as claimed in claim 11 also comprises one or more pharmaceutically acceptable excipient.
CN2009801045488A 2008-02-06 2009-02-06 Pharmaceutical compositions of entacapone, levodopa and carbidopa with improved bioavailability Pending CN101939003A (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
IN262/MUM/2008 2008-02-06
IN262MU2008 2008-02-06
IN263MU2008 2008-02-06
IN263/MUM/2008 2008-02-06
PCT/IB2009/050486 WO2009098661A1 (en) 2008-02-06 2009-02-06 Pharmaceutical compositions of entacapone, levodopa and carbidopa with improved bioavailability

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CN106880607A (en) * 2015-12-15 2017-06-23 北大方正集团有限公司 A kind of oral disnitegration tablet containing Rui Gefeini and preparation method thereof

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PT3188725T (en) * 2014-09-04 2021-01-27 Lobsor Pharmaceuticals Ab Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a comt inhibitor and method of administration thereof
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CN106880607A (en) * 2015-12-15 2017-06-23 北大方正集团有限公司 A kind of oral disnitegration tablet containing Rui Gefeini and preparation method thereof
CN106236720A (en) * 2016-08-29 2016-12-21 海南通用康力制药有限公司 A kind of pharmaceutical composition of entacapone and preparation method thereof

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US8709485B2 (en) 2014-04-29
KR101444979B1 (en) 2014-10-07
EP2252284B1 (en) 2011-05-25
CA2714112C (en) 2015-08-11
KR20100117097A (en) 2010-11-02
JP5466179B2 (en) 2014-04-09
ATE510537T1 (en) 2011-06-15
US9089485B2 (en) 2015-07-28
ZA201005615B (en) 2011-10-26
US20110091558A1 (en) 2011-04-21
US20140187644A1 (en) 2014-07-03
PL2252284T3 (en) 2011-10-31
MX2010008711A (en) 2011-05-03
AU2009211028A1 (en) 2009-08-13
WO2009098661A1 (en) 2009-08-13
JP2011511061A (en) 2011-04-07
EP2252284A1 (en) 2010-11-24
CA2714112A1 (en) 2009-08-13
AU2009211028B2 (en) 2013-12-05
RU2485947C2 (en) 2013-06-27
RU2010136935A (en) 2012-03-20
PT2252284E (en) 2011-08-23
BRPI0908052A2 (en) 2015-08-11
NZ587168A (en) 2011-06-30

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